Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells

Resistance to suppression of multiple serine kinase pathways

Zsuzsanna S. Nagy, Yuling Wang, Rebecca A. Erwin-Cohen, J. Aradi, Brett Monia, Li Hua Wang, Stanislaw M. Stepkowski, Hallgeir Rui, Robert A. Kirken

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G1-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, be constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-2, -7, -9, and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase.

Original languageEnglish
Pages (from-to)819-828
Number of pages10
JournalJournal of Leukocyte Biology
Volume72
Issue number4
Publication statusPublished - Oct 1 2002

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Protein-Serine-Threonine Kinases
Interleukin-2
Transcription Factors
Phosphorylation
Cytokines
T-Lymphocytes
Serine
Transcriptional Activation
Phospho-Specific Antibodies
STAT5 Transcription Factor
Phosphatidylinositol 3-Kinase
Phosphoserine
Interleukin-7
Antisense Oligonucleotides
G1 Phase
Phorbol Esters
Sirolimus
T-Cell Antigen Receptor
Mitogen-Activated Protein Kinases
S Phase

Keywords

  • Janus tyrosine kinase
  • mTor
  • Oligodeoxynucletide
  • Signal transduction
  • T lymphocytes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells : Resistance to suppression of multiple serine kinase pathways. / Nagy, Zsuzsanna S.; Wang, Yuling; Erwin-Cohen, Rebecca A.; Aradi, J.; Monia, Brett; Wang, Li Hua; Stepkowski, Stanislaw M.; Rui, Hallgeir; Kirken, Robert A.

In: Journal of Leukocyte Biology, Vol. 72, No. 4, 01.10.2002, p. 819-828.

Research output: Contribution to journalArticle

Nagy, Zsuzsanna S. ; Wang, Yuling ; Erwin-Cohen, Rebecca A. ; Aradi, J. ; Monia, Brett ; Wang, Li Hua ; Stepkowski, Stanislaw M. ; Rui, Hallgeir ; Kirken, Robert A. / Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells : Resistance to suppression of multiple serine kinase pathways. In: Journal of Leukocyte Biology. 2002 ; Vol. 72, No. 4. pp. 819-828.
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AU - Nagy, Zsuzsanna S.

AU - Wang, Yuling

AU - Erwin-Cohen, Rebecca A.

AU - Aradi, J.

AU - Monia, Brett

AU - Wang, Li Hua

AU - Stepkowski, Stanislaw M.

AU - Rui, Hallgeir

AU - Kirken, Robert A.

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N2 - Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G1-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, be constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-2, -7, -9, and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase.

AB - Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G1-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, be constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-2, -7, -9, and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase.

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KW - mTor

KW - Oligodeoxynucletide

KW - Signal transduction

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